In 1995, Quinn was hired by Saturday Night Live as a writer and featured player. He became a full cast member during the 1997–1998 season. He established himself on the show with characters such as "Lenny the Lion" and "Joe Blow", and did the recurring segment "Colin Quinn Explains the New York Times".[7]

After leaving SNL, Quinn hosted the short-lived The Colin Quinn Show on NBC, which was cancelled after three episodes.

Quinn had greater success with his subsequent show, Tough Crowd with Colin Quinn, which ran on weekdays on Comedy Central from 2002 to 2004. The show featured a panel of four "comedians", with Quinn as host, discussing the social and political issues of the day. The show ran for over 200 episodes.

He was the "unofficial co-host" on the Nick DiPaolo show on the now-defunct 92.3 Free FM in New York City, airing Monday-Friday from noon to three. Quinn and DiPaolo were originally slated to host the show together on WJFK-FM, but the station decided not to pick up the show. Quinn was also a regular guest on The Opie & Anthony Show until its run ended in 2014.

Quinn played Dickie Bailey, the childhood rival to Lenny Feder (Adam Sandler's character) in both Grown Ups films. He also currently recurs as Hermie on the HBO series Girls.

L/Studio announced in February 2015 that Quinn will write and star in an online web series to be hosted on the studio's website. Entitled “Cop Show”, the series satirizes popular New York City crime dramas, namely Law and Order which Quinn has famously never appeared in. Jerry Seinfield, Jim Gaffigan, Michael Che, Jim Norton, Pat Cooper, and Amy Schumer all guest starred on Cop Show episodes.[9]

Quinn made his Broadway debut in 1998 in a one-man show, Colin Quinn: An Irish Wake, co-written with Lou DiMaggio. The show reflected Quinn's upbringing within the Irish-American community of Brooklyn; it was set at a wake in 1976, with Quinn portraying family members and acquaintances who show up for the event.

In 2009, Quinn premiered his second one-man show "My Two Cents", which covers the economic crumbling of the American empire.[10]

In 2010, Quinn premiered his third one-man show Colin Quinn Long Story Short on Broadway, directed by Jerry Seinfeld. The show covered world history from prehistoric times to the present, offering satirical takes on the rise and fall of various world empires. Quinn recorded a special performance of the show that aired on HBO on April 9, 2011.[11]

In 2013, Quinn premiered another one-man show on historical themes, Unconstitutional, which covers the United States Constitution, its creation, and its impact on the American psyche.[12]

Quinn will be starring in his fifth one-man show July 9 - August 16, 2015 at the Cherry Lane Theatre. The show is based upon the experiences chronicled in his book, "The Coloring Book: A Comedian Solves Race Relations in America." It delves into his growing up in the ethnically diverse Park Slope neighborhood of Brooklyn and how it has changed over the years into its current state.[13]

Quinn has gained fame for his account on the social network Twitter, where he usually posts deliberately vacuous statements, often in the form of either inspirational statements or boasts about his celebrity status, that are intended to provoke his readers.[12]